N-{8 4-(Phenyl)-piperazino{9 alkyl-thiazole-5-carboxamides

ABSTRACT

Novel thiazolcarboxamides of the formula   D R A W I N G WHEREIN R is selected from the group consisting of alkyl of 1 to 6 carbon atoms and phenyl, R1 is selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms, n is a whole number from 2 to 5 and X and X1 are individually selected from the group consisting of hydrogen, halogen, trifluoromethyl and alkyl, alkoxy and alkylthio of 1 to 4 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having Alpha -adrenolytic activity and their preparation.

tlnited fitates Patent 1191 Le Martret et al.

[ Mar. 18, 1975 N-[4-(PHENYL)-PIPERAZINO]ALKYL- THIAZOLE-S-CARBOXAMIDES [75] Inventors: Odile Le Martret, Paris; Francois Clemence, Rosny-sous-Bois, both of France 1731 Assigneel 399E59 UQLAF Peristfit e [22] Filed: Mar. 12, 1973 [21] Appl. No.: 340,289

[30] Foreign Application Priority Data Mar. 22, 1972 France 72.10010 [52] US. Cl 260/268 PH, 260/302 R, 424/250 [51] Int. Cl C07d 51/70 [58] Field of Search..... 260/268 PH, 268 H, 268 FT [56] References Cited UNITED STATES PATENTS 2,722,529 11/1955 Fleming et a1 260/268 PH 3,005,821 10/1961 Shin Hayao 260/268 PH 3,712,893 1/1973 Mauvernay et a1. 260/268 FT 3,761,481 9/1973 Nakanishi et a1. 260/268 FT Primary Examiner-Donald G. Daus Assistant E.raminerlose Tovar Attorney, Agent, or FirmHammond & Littell ABSTRACT thiazolcarboxarnides Novel of the lorm ula 8 Claims, N0 Drawings N-[4-(PHENYL)-PIPERAZINOJALKYL- THIAZOLE-S-CARBOXAMIDES STATE OF THE ART Belgium patent No. 736,219 describes various thiazol-S-carboxylic acids having vasodilatatory and hypolipemiant activity. French BSM patent No. 7590 teaches aryl piperazinyl alkylene carboxamides of thiophenes which possess anti-depressive, analgesic antiinflammatory and diuretic activity.

OBJECTS OF THE INVENTION THE INVENTION The novel products of the invention are selected from the group consisting of thiazolcarboxamides of the formula i l l r i wherein R is selected from the group consisting of alkyl of l to 6 carbon atoms and phenyl, R is selected from the group consisting of hydrogen and alkyl of l to 4 carbon atoms, n is a whole number from 2 to and X and X are individually selected from the group consisting of hydrogen, halogen, trifluoromethyl and alkyl, alkoxy and alkylthio of l to 4 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts.

Among the preferred substituents are R as alkyl such as methyl, ethyl, n-propyl, n-butyl or n-pentyl, R X and X, as alkyl such as methyl or ethyl and X and X, as halogens such as fluorine, bromine or chlorine or alkoxy or alkylthio such as methoxy, ethoxy, ethylthio or methylthio. The preferred compounds of formula I are those where X is o-methoxy, X is hydrogen, R is ethyl, propyl or phenyl and R, is hydrogen or methyl and n is 2 or 4.

The non-toxic, pharmaceutically acceptable acid addition salts may be derived from an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid and organic acids such as acetic acid, benzoic acid, tartaric acid, fumaric acid, maleic acid, methane sulfonic acid or p-toluenesulfonic acid.

The process of the invention for the preparation of the compounds of formula I comprises reacting a thiazol-S-carboxylic acid of the formula A OOH wherein R is alkyl of l to 6 carbon atoms or phenyl or a functional derivative thereof with a phenylpiperazine of the formula wherein R X, X and n have the above definitions to form the desired thiazol5-carboxamide of formula I which may be treated with an acid to form the corresponding acid addition salt.

The functional derivatives of the thiazol-S-carboxylic acids of formula [I may be the anhydride, the acid chloride, lower alkyl ester or mixed acid anhydride which have been classically used to form amides.

When using the free acid of formula II, the reaction is preferably effected by heating with the amine of formula III in the presence of a dehydrating agent such as dicyclohexylcarbodiimide. When using a lower alkyl ester of the acid of formula II, the reaction may be effected by simply heating with the amine of formula III.

When using the acid chloride or anhydride, the reaction is effected in an inert organic solvent such as aromatic hydrocarbons like toluene, xylene or benzene or ethyl ether or chloroform. If a mixed anhyride is used, it preferably is a mixed carbonic acid anhydride of the formula R IV wherein R has the above definition and R is alkyl of l to 6 carbon atoms and is preferably prepared by reacting an alkyl chloroformate of the formula Cl--COOR with a salt, i.e. triethylamine, of the acid of formula II. The reaction with the amine of formula III is preferably effected with a solvent such as acetone.

The amines of formula III used as starting materials are known or easily prepared by known processes. For example, when R is hydrogen, a halonitrile of the formula Hal-(CH ,CN v wherein Hal is a halogen and n is 2 to 5 is reacted with a phenylpiperazine of the formula NC- (ca VII and the nitrile may be reduced as taught by Mull et al [.I. Med. Pharm. Chem., Vol. (1962), p. 944-949]. Where R is alkyl, the amines may be prepared as described in Example 4.

The novel a-adrenolytic compositions of the invention are comprised of an effective amount of a compound of formula 1 or a non-toxic, pharmaceutically acceptable acid addition salt thereof and a pharmaceutical carrier. The compositions may be in the form of tablets, sublingual tablets, dragees, capsules, gelules, drinkable solutes or suspensions or suppositories or in the form of injectable solution or suspensions.

water, dried over magnesium sulfate and evaporated to dryness. The residue was crystallized from isopropyl ether to obtain 8.4 g of N-B-[4-(o-methoxyphenyl)-1 piperazinyl]-ethyl-2-n-propy1thiazol-5-carboxamide in the form of colorless crystals melting at 113C.

5 ml of an ethanolic hydrochloric acid solution titrating 4.29 N were added to a solution of 8.4 g of N-fl- Analysis: C H N O S; molecular weight 388.53 Calculated: 7zC 14.42 %S 8.23 Found: 14.32 8.16

-(o-methoxyphenyl)-1 -piperazinyl]-ethyl-2-npropylthiazol-5-carboxamide in 43 ml of ethanol and the mixture was filtered. The recovered precipitate was crystallized from ethanol to obtain 7.4 g of N-B-[4'-(omethoxyphenyl)-l '-piperazinyll-ethyl-2-npropylthiazol-S-carboxamide hydrochloride melting at 180C. The product occurred as colorless crystals soluble in water, methanol and ethanol and insoluble in benzene and ethyl ether.

Analysis: C H N O S HCl; molecular weight 424.98

Calculated: 71C 56.52 %H 6.88 %Cl 8.34 %N 13.18 705 7.55

Found: 56.3 6.7 8.4 13.1 7.4

The compositions have an a-adrenolytic activEy ahd EXAMPLE 2 are distinguished from the free acids from which the carboxamides of formula 1 are derived by not presenting any notable peripheric vasodilatatory activity while manifesting a sedative activity.

The novel method ofthe invention for treating hypertension in warm-blooded animals comprises administering to warm-blooded animals a hypotensively effective amount of a compound of formula I or a non-toxic, pharmaceutically acceptable acid addition salt thereof. The products may be administered orally, perlingerally, parenterally or rectally. The usual daily dose is 0.2 to 10 mg/kg depending upon the product and the method of administration.

In the following examples there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

EXAMPLE 1 N-B-[4-(o-methoxyphenyl)-1-piperazinyl]-ethyl-2-npropylthiazol-5-carboxamide A solution of 8.7 g of ethyl chloroformate in ml of acetone was added with stirring and cooling to 6 to 8C to a suspension of 11.1 g of 2-n-propyl-5- carboxythiazol in 80 ml of acetone to which a solution of 7.2 g of triethylamine in 30 ml of acetone had been added. After returning the mixture to room temperature, the mixture was stirred for 30 minutes and then was filtered to remove the triethylamine hydrochloride formed. The filtrate was cooled to 8C and a solution of 11.4 g of 4-(o-methoxyphenyl)-l-(B-aminoethyD- piperazine in 30 ml of acetone was added thereto. The mixture stood for 48 hours and then the acetone was evaporated. The oil residue was taken up in 300 m1 of ethyl ether and 20 m1 of water and the ether phase was washed with a 20% aqueous potassium carbonate solution until the wash water were neutral and then with N-B-[4'-( o-methoxyphenyl )-l -piperazinyl]-ethyl-2- ethylthiazol-S-carboxamide A solution of 3.2 g of triethylamine in 10 ml of acetone was added to a suspension of 4.5 g of 2-ethyl5- carboxythiazole in 30 ml of acetone and after cooling the mixture of 6C, a solution of 3.3 g of ethyl chloroformate in 15 ml of acetone was added with stirring while keeping the temperature at 6 to 8C. After raising the temperature to room temperature, the mixture was stirred for 30 minutes and then filtered to remove the precipitate formed. The filtrate was cooled to 8C and asolution of 5.9 g of 4-(o-methoxyphenyl)-1-(B- aminoethyl)-piperazine in 15 ml of acetone was added thereto. The mixture stood for 16 hours and the acetone was then evaporated. The oily residue was taken up in 100 ml of methylene chloride and 10 ml of water and the organic phase was washed with aqueous 10% potassium carbonate solution until the wash waters were neutral, then with water, dried over magnesium sulfate and evaporated to dryness. The residue was taken up in 20 m1 of isopropyl ether and the solution was filtered. The precipitate was crystallized from cyclohexane to obtain 4.4 g of N-B-[4'-(omethoxyphenyl)-l -piperazinyll-ethyl-Z-ethylthiazol- S-carboxamide melting at 110C. The product occurred in the form of colorless-crystals soluble in methanol, ethanol, acetone and chloroform and insoluble in water.

Analysis: C l-1 M0 5; Calculated: C 6093 Found: 6 l 1 molecular weight 374.49

%l-l 7.00 7N 14.96 7:5 8.56

EXAMPLE 4 N-methyl-N-B-l4-(o-methoxyphenyl)-1'-piperazinyllethyl-2-a-propy1thiazol-5-earhoxamide STEP A: 4-(o-metltoxyphenyl)-l-chloroethyL piperazine .HCl

79.4 ml of ethanolic 3.15 N hydrochloric acid were added to a solution of 29.5 g of 4-(o-methoxyphenyl) Analysis: C,,,H ,,N O S HCl; molecular weight 410.96

Calculated: /rC 55.53 71H 6.62 /(C1 8.63 7(N 13.63 7L5 7.80

Found: 55.6 6.7 8.6 13.4 7.7

EXAMPLE 3 N-B[ 4'(o-methoxyphenyl)-l '-piperazinyl l-ethyl-2- phenylthiazol-S-carboxamide A solution of 3.65 g of triethylamine in ml ofacetone was added to a suspension of 6.8 g of 2-phenyl-5- carboxythiazole [prepared by process of J.A.C.S., Vol. 65 (1943), p. 2167] in 35 m1 ofacetone and after cooling to 3C, a solution of 3.8 g of ethyl chloroformate in ml of acetone was added thereto. The solution stood for minutes at room temperature and the precipitate formed was filtered off. The filtrate was cooled to 6C and then a solution of 6.8 g of 4-(o-methoxyphenyl)-l- (B-aminoethyl)-piperazine in ml of acetone was added thereto while maintaining the temperature at 6 to 9C. The mixture was then allowed to stand overnight at room temperature and was filtered. The precipitate recovered was washed with acetone to obtain 4 g of colorless crystals melting at 152C. The filtrate was evaporated to dryness and the residue was dissolved in 100 ml of methylene chloride. The organic solution was washed with water, then with aqueous 10% potassium carbonate solution and finally with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was crystallized from ether, recovered by filtration and crystallized from ethanol to obtain 3 g of raw product melting at l5l-152C. The combined products were crystallized from ethanol to obtain 6.2 g of N-B-[4-(omethoxyphenyl)-1'-piperazinyll-ethyl-2-phenylthiazol- 5-carboxamide melting at 152C. The product occurred as colorless crystals soluble in chloroform, slightly soluble in ethanol and N hydrochloric acid and in soluble in water and ether.

Analysis: H,,,N O,S; molecular weight =422.54 Calculated: 71C 65.37 /(H 6.20 71N 13.26 7(5 7.59 Found: 65.3 6.1 13.2 7.8

l-hydroxyethyl piperazine (described in US. Pat. No. 2,836,595) in 1,000 ml of ethyl ether and the mixture was filtered. The precipitate recovered was washed with ethyl ether to obtain 38 g of 4-(o-methoxyphenyl 1-hydroxyethyl-piperazine.l-lCl. The said product was suspended in 370 ml of 1,1-dioxide of tetrahydrothiophene and after adding 13.3 ml of thionyl chloride to the solution, the mixture was heated at C for 20 minutes. After cooling, the solution was poured into 2 liters ofbenzene and the mixture was filtered. The precipitate recovered was crystallized from ethanol to obtain 20.2 g of 4-(o-methoxyphenyl)-1-ch1oroethylpiperazine hydrochloride melting at C. The free base was obtained by treating the hydrochloride with potassium carbonate and it melted at 36C.

STEP 8: 4-(o-methoxyphenyl)-l-(B- methylaminoethyl)-piperazine 8 ml of ethanol were added to a mixture of 8.9 g of 4-(o-methoxyphenyl)-l-chloroethyl-piperazine .HCl in 20 g of an aqueous solution of 34.88% methylamine and the mixture was stirred for 1 hour at room temperature and then for 4 hours at reflux. The ethanol was evaporated and after cooling the mixture, 5 g ofsodium hydroxide pellets were added thereto. The mixture was extracted with ethyl ether and the extracts were dried over potassium carbonate and the solvent was evaporated. The oily residue was distilled to obtain 2.6 g of 4-(o-methoxyphenyl l -(B-methylaminoethyl)- piperazine in the form of a yellow oil boiling at 153C under 0.2 mm Hg. The oil was soluble in ethanol and ethyl ether and slightly soluble in water.

Analysis: Calculated: Found:

( H- N 0; molecular weight 249.36

in 5 ml of acetone was added thereto. The mixture 1 stood overnight and the acetone was then evaporated. The residue was taken up in 30 m1 of methylene chlo- Analysis: C- H ClMO S; molecular wei ht 459 Calculated: %C 60.18 (7LH 5.93 (C1772 7rN 12.21 Found: 60.2 5.7 7.9 12.1

ride and ml of water and the organic phase was washed with an aqueous potassium carbonate solution, then with water, dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed over silica gel and eluted with a 6-4 acetonecyclohexane mixture to obtain 1.04 g of N-methyl-NB- [4-(o-methoxyphenyl)-1-piperazinyl]-ethyl-2-npropyl-thiazol-S-carboxamide in the form of colorless crystals melting at 65C.

of magnesium carbonate was heated for 4 hours at 60C and the precipitate formed was removed by filtration. The dioxane was distilled from the filtrate and the residue was taken up in 665 ml of a l1 ethyl etherwater mixture. The ether phase was recovered by decantation and was washed with aqueous 10% hydrochloric acid solution and then with water until the wash waters were neutral. dried over magnesium sulfate and distilled to dryness. The residue was distilled to obtain The latter product and 0.50 g of the said product pro- 10 57 g of ethyl 2-n-propylthiazol-5-carboxylate boiling at duced in another preparation were dissolved in 7 ml of 95-106C under 0.5 mm Hg. ethanol and 1.3 ml of an ethanolic 3.15 N hydrochloric STEP C: N-B-[4-(o-methoxyphenyl)-l acid solution were added thereto. The precipitate piperazinyl]-ethyl-2-n-propylthiazol-5-carboxamide formed was recovered by filtration and was crystallized 7 g of 4-(o-methoxyphenyl)-l-(,B-aminoethyl)- fmm i50131013111101 to Obtain g of Y -B-l piperazine were melted at C and 6 g of ethyl 2-n- (o-methoxyphenylyl-piperazinyl]-ethyl-2-npropylthiazol-5-carboxylate were added thereto. The propylthiazol-S-carboxamide hydrochloride melting at ixtur was heated for 3 /2 hours at 125C under a ni- 185C. The product occurred as colorless crystals solutrogen atmosphere and after returning to room temperble in chloroform and water, slightly soluble in ethanol ature, 20 ml of ethyl ether were added thereto. The and insoluble in ether. 20 mixture was ground and allowed to stand overnight.

Analysis: ,H;, (lN,,O S; molecular weight 439.02 Calculated: 71C 57.45 "/(H 7.12 "/(N 12.76 VrCl 8.07 /(S 7.30 Found: 57.1 7.1 12.6 8.1 7.5

EXAMPLE 5 The precipitate was recovered by filtration and was o methox hen l i erazin l but washed with ethyl ether and crystallized from isopropyl g g ggg z p p y 1 y 0 ether to obtain 5.5 g of N-B-[4:(o-methoxyphenyl}1 5.1 g of triethylamine were added to a solution of 8.6 PlPeraZmyll'ethyl'z'n'propylthlazol'scarboxamlde g of 2-n-propyl-5-carboxythiazole in ml of toluene demlcal to the Product of Example and then a solution of 5.5 g of ethyl chloroformate in EXAMPLE 7 20 ml of toluene was added thereto at 20C. Then, a Solution f 15 g f 4 (o methoxyphenyl) 1 (5 xi An in ectable SOlUtIOH WHS prepared by dissolving l0 aminobutyU-piperazine (described in U.S. Pat. No. mg (calculated tree. bilge) of f 3,398,151 in 50 ml of toluene was added and the mix- YP PY 'PP fl -j Y" ture was stirred for 15 hours at room temperature. The 5-clrlmflmlde hydwqhlonde l Sufllclem aqueous solution was washed with water, dried and concenexclplent t0 Obtain final of 3 trated to dryness and the residue was crystallized from 40 EXAMPLE 8 an isopropyl ether-isopropanol mixture to obtain 7.5 g i of N-8-[4-(o-methoxyphenyl)-l -piperazinyl]-butyl-2- Tablets were P p y throulghadmvfmg of 50 mg n-propylthiazol-S-carboxamide melting at 100C. 0f 'l yP y 'p p y l' y ethylthiazole-S-carboxamide hydrochloride and 500 4g mg of an excipient consisting of lactose, amidon. talc and magnesium stearate. Analysis: C H Mox siainolegiulla; wright 1 6 .2 /15 7 70 -gL gf 2 PHARMACOLOGICAL DATA A. In vitro adrenolytic activity EXAMPLE 6 50 A withdrawn portion of the duodenum of a rabbit was placed in a bath containing oxygenated tyrode liq- -B-[ yp yh- -p p y ly uid at 37C and the sensibility of the duodenum to a propylthiazole-5-Carboxami e dose of 0.01 B/ml for 30 seconds of adrenaline was de- STEP A: Thiobutyramide termined. The test product was contacted with the A mixture CH1 8 of butyronitrile and 35 g ofdlethyl' organ for 30 seconds and immediately afterwards, the amine was heated to 50-60C and the solution was sat- Qrgan was bj t d to d li t a d e f 0,01 urated by bubbling hydrogen sulfide therethrough. B/ f 30 d Th d se f the test compound After the addition in 500 m of at the mixture Was which inhibited 50% of decontractions due to adrenaextracted with ethyl ether and the ether phase was line (DA was determined. The test products used in washed with aqueous 10% hydrochloric acid solution solution in physiological serum and the muscle contracand then with water until the wash waters were neutral. tions were recorded on a myograph. The results are The ether phase was dried over magnesium sulfate and shown in Table I. the ethyl ether was removed by distillation to obtain 87 TABLE I g of thiobutyramide which was used as is for the next step.

STEP B: Ethyl 2-n-propylthiazol-5-carboxylate Product m A mixture of 38 g of thiobutyramide, 54.2 g of ethyl N-B-l -t yp y J- plperazlnyll-ethyl-Z-n-propyl- 0.5

2-formyl-2-chloro-acetate, ml of dioxane and 22 g thiazol-S-carboxamide hydro- TABLE l-Continued Product DA,,,, in -y/ml chloride (compound A) N-B-[4'-( o-methoxyphcnyl I piperazinyll-ethyl-l-cthylthiazol-S-carboxamide hydrochloride (compound B) N-methyl-NB-M'-(o-methoxyphenyl J-l -piperazinyllethyl-Z-npropylthiazol-S-carboxamidc hydrochloride (compound C) ().l to 0,5

TABLE II Products DA in mg/kg A 0.] to 0.25 B 0.1 0.5

thiazol-5-carboxamidc hydro- (intrapcritoneal) chloride (compound D) thiazol-5-curboxamide (compound El The results of Table II show that the test products have an important "in vivo adrenolytic activity at a dose ofO.l to 1.0 mg/kg.

C. Hypotensive activity The test products were administered intravenously (juglar vein) to groups ol rats and the level of the carotid blood pressure was recorded. The DA dose. dose which reduced by ot'carotidien pressure, was determined 30 minutes after administration of the product. The results are reported in Table Ill.

TABLE III DA in mg/kg Product at 30 mm A 0.25 to 0.5 B 0.5 C 0.5 D 0.5 to l (intraperitoneal) TABLE IV DL in mg/kg lntralntraperi- Product venous toneal D insoluble 325 Various modifications of the products and compositions of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is to be limited only as defined in the appended claims.

We claim:

1. A compound selected from the group consisting of .thiazolcarboxamides of the formula wherein R is selected from the group consisting of alkyl of l to 6 carbon atoms and phenyl, R is selected from the group consisting of hydrogen and alkyl of l to 4 carbon atoms, 11 is a whole number from 2 to 5 and X and X are individually selected from the group consisting of hydrogen, halogen, trifluoromethyl and alkyl, alkoxy and alkylthio of l to 4 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts.

2. A compound of claim 1 wherein X, is hydrogen and X is o-methoxy.

3. A compound ofclaim 2 wherein R is selected from the group consisting of ethyl, propyl and phenyl and R, is selected from the group consisting of hydrogen and methyl and n is 2 or 4.

4. A compound of claim 1 selected from the group consisting ol N-B-l4-(o-methoxyphenyl)- l piperazinyl l-ethyl-Z-n-propylthiazol-S-carboxamide and its non-toxic. pharmaceutically acceptable acid ad dition salts.

5. A compound of claim 1 selected from the group consisting of N-B-[4-(o-methoxyphenyl)-l piperazinyl]-ethyl-2-ethylthiazol-5-carboxamide and its non-toxic, pharmaceutically acceptable acid addition salts.

6. A compound of claim 1 selected from the group consisting of N-B-[4'-(o-methoxyphenyl I piperazinyl]-ethyl-2-phenylthiazol-S-carboxamide and its non-toxic, pharmaceutically acceptable acid addition salts.

7. A compound of claim 1 selected from the group consisting of N-methyl-N-B-[4'-(o-methoxyphenyl)- l piperazinyl]-ethyl-Z-n-propylthiazol-S-carboxamide and its non-toxic, pharmaceutically acceptable acid addition salts.

8. A compound of claim 1 selected from the group consisting of N-6-[4-(o-methoxyphenyl)-l piperazinyll-butyl-2-n-propylthiazol-S-carboxamide and its non-toxic, pharmaceutically acceptable acid addition salts. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THIAZOLCARBOXAMIDES OF THE FORMULA
 2. A compound of claim 1 wherein X1 is hydrogen and X is o-methoxy.
 3. A compound of claim 2 wherein R is selected from the group consisting of ethyl, propyl and phenyl and R1 is selected from the group consisting of hydrogen and methyl and n is 2 or
 4. 4. A compound of claim 1 selected from the group consisting of N- Beta -(4''-(o-methoxyphenyl)-1''-piperazinyl)-ethyl-2-n-propylthiazol-5-carboxamide and its non-toxic, pharmaceutically acceptable acid addition salts.
 5. A compound of claim 1 selected from the group consisting of N- Beta -(4''-(o-methoxyphenyl)-1''-piperazinyl)-ethyl-2-ethylthiazol-5-carboxamide and its non-toxic, pharmaceutically acceptable acid addition salts.
 6. A compound of claim 1 selected from the group consisting of N- Beta -(4''-(o-methoxyphenyl)-1''-piperazinyl)-ethyl-2-phenylthiazol-5-carboxamide and its non-toxic, pharmaceutically acceptable acid addition salts.
 7. A compound of claim 1 selected from the group consisting of N-methyl-N- Beta -(4''-(o-methoxyphenyl)-1''-piperazinyl)-ethyl-2-n-propylthiazol-5-carboxamide and its non-toxic, pharmaceutically acceptable acid addition salts.
 8. A compound of claim 1 selected from the group consisting of N- delta -(4''-(o-methoxyphenyl)-1''-piperazinyl)-butyl-2-n-propylthiazol-5-carboxamide and its non-toxic, pharmaceutically acceptable acid addition salts. 